The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by enteroendocrine cells in response to nutrients like fat and glucose and enhance glucose-induced release of insulin from pancreatic β-cells (1,2). GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent enhancement of insulin secretion, induction of β-cell proliferation, and enhanced resistance to β-cell apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of bone resorption. GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).
The effects of GIP and GLP-1 are mediated through specific 7-transmembrane-domain G-protein coupled receptors, GIPR and GLP-1R, respectively (3). Activation of GIPR or GLP-1R is coupled to increases in cAMP and intracellular Ca2+ levels, as well as activation of PI-3K, Epac 2, PKA, PKB, MAPK and phospholipase A2 and finally leads to enhanced exocytosis of insulin-containing granules (4).
In diabetes mellitus type 2 (T2D), a chronic metabolic disorder characterized by insulin resistance and progressive dysfunction of pancreatic islet cells, the meal-stimulated insulin secretion from β-cells is reduced and fails to meet the demands of the insulin-resistant state. Interestingly, the insulinotropic action of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is impaired in type 2 diabetic patients while the effect of glucagon-like peptide-1 (GLP-1) is vastly preserved (1, 10).
Findings in insulinoma cells (5-7) and rodent models (8, 9) indicate that activation of the incretin receptors promotes proliferation and survival of β-cells. This observation as well as studies demonstrating that only the insulinotropic effect of GIP is greatly reduced while GLP-1 functions normally (1) initiated the ongoing development of incretin-based therapies such as incretin mimetics, GLP-1 analogues and inhibitors of the enzyme dipeptidyl-peptidase-4 (DPP-4), which inactivates incretins (reviewed in (2)). The reasons for the reduced response to GIP in T2D are unclear, but it was suggested that impaired GIP action might be involved in the early pathogenesis of type 2 diabetes mellitus (10).
DE 198 36 382 C2 discloses a transgenic mouse containing an altered GIPR which binds GIP but does not induce signalling after binding GIP (11). The transgenic mice expressing the altered GIPR in the β-cells of the pancreas develop a severe diabetes during the first month of their lives (11). Due to this early onset of diabetes, no long-term studies of disturbed GIP/GIPR function in the absence of glucose toxicity can be performed in the mouse model.
Thus, there is a need in the art for improved tools and methods for studying diabetes mellitus, in particular the role of GIP and the involvement of its impaired insulinotropic action in the pathogenesis of type 2 diabetes mellitus (T2D).